AdvancesManagement

in Psychiatric
Treatment (2005), vol.
11, 101106
of clozapine-resistant
schizophrenia

Management of clozapine-resistant
schizophrenia
Rob W. Kerwin & Anusha Bolonna

Abstract The incidence of treatment resistance in schizophrenia (failure to respond to antipsychotic therapy) is
about 20%. Factors that may contribute to it include non-adherence (non-compliance) to treatment,
comorbid conditions and medication side-effects. The National Institute for Clinical Excellence
recommends that clozapine be used for schizophrenia resistant to another atypical antipsychotic. Here
we focus on patients who are also resistant to clozapine given in adequate dosage for sufficient duration.
Switching from clozapine to a previously untried atypical (e.g. olanzapine, risperidone, quetiapine)
might be of benefit in partial treatment resistance. In more difficult cases, augmentation of clozapine
with benzamides (sulpiride, amisulpride) and anti-epileptics (lamotrigine) shows some success. In extreme
treatment resistance, a strategy is recommended that combines the proven best drug for the particular
patient and psychosocial treatments.

This article is the first of two in this issue in the series introduced
by Robin McCreadies editorial Schizophrenia revisited
(McCreadie, 2004). In the second, Connolly & Kelly (2005) discuss
physical health and lifestyle. Previous contributions have considered
environmental influences (Leask, 2004), implementation of the
NICE schizophrenia guidelines (Rowlands, 2004), cognitive deficits
in first-episode schizophrenia (Gopal & Variend, 2005) and early
intervention in psychosis (Singh & Fisher, 2005).

In general, all patients with schizophrenia could be

considered treatment resistant, since full remission
is unusual in this disorder. In order to create specific
treatment algorithms for patients that are more
difficult to treat, it is necessary to define treatment
resistance. Kane (1996) specified the following
criteria for treatment resistance:

available medications and other treatments are

not useful in alleviating the target symptoms
of schizophrenia (not only the positive and
negative symptoms, but also disorganised
or violent/aggressive behaviour, thought
disorder and suicidal ideation);
occurrence of adverse side-effects of medication;
non-adherence to current treatment;
presence of comorbid conditions such as
substance misuse;
failure of maintenance and relapse despite
seemingly adequate doses of antipsychotics.

In addition, arbitrary defining criteria include

failure to respond to at least two neuroleptic drugs
equivalent to 600 mg chlorpromazine per day for

more than 4 weeks (Juarez-Reyes et al, 1995). In

clinical trial and audit settings, the most frequently
used criteria are those adopted by Kane et al (1988)
for their seminal trial of clozapine v. chlorpromazine
in treatment-refractory schizophrenia. In this trial,
patients were classified as resistant to treatment if:
1 they had not demonstrated improvement after
three periods of treatment with neuroleptics
(from two or more different chemical classes)
in the previous 5 years equivalent to 1000 mg
per day of chlorpromazine for 6 weeks;
2 patients had had no episodes of good functioning in the previous 5 years.
Using these criteria, Kane et al found the incidence
of treatment resistance in schizophrenia to be 20%.

Management with clozapine

This article focuses principally on the pharmacological management of treatment resistance. However,
before initiating clozapine therapy, some basic
principles should be adhered to, such as assessing
non-adherence, re-evaluating the diagnosis,
considering organic contributions to the diagnosis
and assessing comorbidity (Morrison, 1996).
The evidence for clozapine as a superior treatment
for schizophrenia is consistent and is the subject of
a number of reviews and meta-analyses (Kane, 1992;
Meltzer, 1992; Brambilla et al, 2002; Iqbal et al, 2003).
Primary references for clozapines superior efficacy

Rob W. Kerwin is Professor and Head of the Section of Clinical Neuropharmacology at the Institute of Psychiatry (De
Crespigny Park, London SE5 8AF, UK. E-mail: r.kerwin@iop.kcl.ac.uk). His interests lie in all aspects of antipsychotic clinical
psychopharmacology. Anusha Bolonna is an honorary research fellow at the Institute, with special interest in the genetics of
drug response in schizophrenia.

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101

Kerwin & Bolonna

Table 1 Symptom domains of schizophrenia targeted by antipsychotics (after Pantelis & Lambert, 2003)
Symptom domain

Clinical features

Comments

Positive

Delusions, hallucinations, formal

thought disorder

SGAs FGAs. Clozapine has superior

efficacy in treatment-resistant patients

Negative

Avolition, apathy, anhedonia,

affective blunting, poverty of speech

SGAs > FGAs. Few studies specifically examine

negative symptoms as primary outcome, but
exceptions are studies of amisulpride

Cognitive

Deficits in memory, attention, executive

function, judgement and insight

SGAs > FGAs. Different SGAs may have

different effects on cognition

Affective

Altered stability of mood, manic-like

symptoms

SGAs > FGAs. Some evidence that clozapine

and olanzapine are effective

Suicidality

Suicidal ideation and behaviour

Clozapine > olanzapine. No evidence available

for other SGAs and FGAs

Behavioural

Social withdrawal, antisocial behaviour,

incoherent and odd conversation

Limited research available to assess drug

effects in this domain

Social and role

functioning,
quality of life

Social interaction deficits, impaired

activities of daily living

More research required. Some suggestion that

SGAs superior to FGAs

FGA, first-generation antipsychotic; SGA, second-generation antipsychotic; >, more effective than; >, as effective as or
more effective than.

are cited in these reviews, but pivotal publications

include a clinical trial of its use in treatment-resistant
schizophrenia (Kane et al, 1988) and a meta-analysis
of randomised controlled trials of clozapine
(Wahlbeck et al, 1999).
Another further useful practical guide to the drugs
use in treatment-resistant schizophrenia is a review
by Pantelis & Lambert (2003). In this, the authors
suggest that treatment resistance is related to several
symptom domains (Table 1) and they offer a threephase algorithm for the pharmacological management of incompletely recovered (treatment-resistant)
patients (Fig. 1).

Managing clozapine-resistant
patients
The most comprehensive review on this topic was
published by Barnes et al (1996). Again, basic factors
for clozapine-resistance highlighted in this review
include comorbid drug misuse, poor adherence,
inadequate duration of treatment and/or inadequate
dosage. As Barnes et al note, two of these factors
warrant further explanation.
The first is inadequate duration of treatment. It is
accepted that a proportion of patients have a
delayed response to clozapine (Meltzer, 1992).
Meltzer concluded that 30% would respond by
6 weeks, a further 20% by 3 months and an
additional 1020% by 6 months. Therefore, it seems
reasonable to try clozapine monotherapy for
6 months. This leaves a residue of 30% of patients
for whom it must be decided whether to persevere

102

with clozapine, consider various augmentation

strategies or to cease clozapine therapy.

Phase 1

Exclude confounders


Ensure adequacy of at least

two previous trials


Optimise current dosage

and treat side-effects

Phase 2

If second-generation antipsychotics were not

previously used, try olanzapine, risperidone,
quetiapine or amisulpride for 68 weeks


If no response, start clozapine

(referral required).
Enable psychosocial treatments

Phase 3

If no response to clozapine,
reinstate best prior medication
and adjunctive therapy


Consider electroconvulsive therapy

Fig. 1 Pharmacological management of incompletely

recovered patients (after Pantelis & Lambert, 2003).

Advances in Psychiatric Treatment (2005), vol. 11. http://apt.rcpsych.org/

Management of clozapine-resistant schizophrenia

The second factor is inadequate dosage. Clozapine

dosage can be a relatively complicated issue. In
particular, there is no meaningful relationship
between clozapine plasma levels and clinical
response. However, there is a consensus in the
literature that a plasma level of about 350450 ng/
ml has to be attained before the patient is considered
to be non-respondent to clozapine (Perry et al, 1991;
Potkin et al, 1994).
Clozapine is also subject to considerable metabolism by the cytochrome P450 (CYP) enzyme system
(Aitchison et al, 2000). There are numerous variants
of the genes encoding the CYP enzyme family within
the general population, resulting in complex
individual genetic profiles and a variable response
to drugs metabolised by these enzymes (Ma et al,
2004). Therefore, in clinical practice, patients can
be very susceptible to side-effects at drug dose levels
that appear to be below the threshold for clinical
efficacy.

Augmentation of clozapine
A frequent treatment strategy for clozapine-resistant
patients with schizophrenia is the use of specific
augmentors that are suitable for adjunctive therapy.
Clozapine is a polyvalent drug but it lacks highpotency dopamine receptor blockade (Kerwin &
Osborne, 2000). Therefore, there has been interest in
using as augmentors substituted benzamides with
highly selective dopamine receptor blocking profiles
(Kerwin, 2000). Augmentation strategies incorporating sulpiride are well documented. The authors
of one study of sulpiride augmentation in 28 patients
partially responsive to clozapine (Shiloh et al, 1997)
noted a mean reduction of about 4050% in various
clinical response scores (Brief Psychiatric Rating
Scale and Scale for the Assessment of Positive
Symptoms).
Several groups have been interested in mimicking
this study with amisulpride, a relative of sulpiride
that is even more selective at the dopamine D2
receptor. A case series by Zink et al (2004) showed
improvement in previously treatment-resistant
symptoms following a combined treatment strategy
of clozapine and amisulpride. In addition, our
group performed an open trial of amisulpride
augmentation in a long-term (52 weeks) study.
Significant improvement was observed in half of the
patients, with no additional side-effects. Moreover,
this study monitored plasma levels to determine
whether this was a pharmacokinetic interaction.

The pharmacogenetics of clozapine treatment has been

discussed in a previous issue of APT: see Tsapakis et al
(2004). Ed.

Clozapine levels did not change throughout the

duration of the trial, suggesting a pharmacodynamic
interaction (Munro et al, 2004).

Augmentation with anti-epileptics

A glutamate hyperfunction hypothesis of schizophrenia has generated interest in the role of
glutamate release inhibitors as clozapine augmentors. In a study of 26 treatment-resistant patients
receiving lamotrigine (17) or topirimate (9) in
addition to their existing antipsychotic treatment (a
variety of antipsychotics), a significant improvement
was observed when lamotrigine was added to
risperidone, haloperidol, olanzapine or flupenthixol. However, no significant effect was
observed in patients receiving topirimate augmentation in addition to clozapine, olanzapine,
haloperidol or flupenthixol (Dursun & Deakin,
2001). The therapeutic effects of lamotrigine
augmentation were also assessed in a rigorous
randomised placebo-controlled cross-over study of
34 clozapine-resistant patients (Tiihonen et al, 2003).
In this 14-week study, lamotrigine treatment
significantly improved positive symptoms and
general psychopathological symptoms, but had no
effect on negative symptoms. The authors suggested
that this was the first time a non-dopamine
antagonist had proven efficacy in schizophrenia,
giving further credence to the hyperglutamate
neurotransmission hypothesis for the generation of
positive symptoms in the disorder.

Are other atypicals, alone

or in combination, of use?
Other atypical antipsychotics were not trialled in
the pre-registration phase for their efficacy in
treatment resistance. However, there have been a
number of phase IV trials that have examined this
possibility.

Risperidone
The earliest study examining the possibility that
risperidone may be of use in treatment resistance
was conducted by Bondolfi et al (1998). This 8-week
study of risperidone and clozapine concluded that
the two drugs are comparable. However, the study
has been criticised for its rapid titration schedule of
1 week, which may have led to clozapine intolerance
and therefore to patients receiving suboptimal doses
of the drug. Later studies include that by Wahlbeck
et al (2000), which was a 10-week open-label trial of
risperidone v. clozapine using a 20% decrease in
Positive and Negative Symptom Scale score as the

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103

Kerwin & Bolonna

definition of clinical improvement. Intention-to-treat

analysis did not identify significant differences
between the two groups, but there was an unusually
high dropout rate for clozapine (5 of 10 participants),
seriously reducing the power of the study. To date,
there has been no large, randomised, pragmatic trial
of risperidone v. clozapine that has sufficient power
to detect a difference between the treatments.

Olanzapine
The most informative study of olanzapine in
treatment resistance is likely to be that by Conley
et al (1998). This reproduced the methodology of
the pivotal Kane et al (1988) study of clozapine but
concluded that olanzapine was no better than
chlorpromazine in treatment resistance. Additional
studies using olanzapine following treatment
failures with other antipsychotics (switching
studies) have proved disappointing. However, one
(Lindenmayer et al, 2002), although showing that
olanzapine was not a useful switch drug for general
psychopathological symptoms, did demonstrate an
improvement in symptoms related to cognitive
function. In a further switching study, Conley et al
(1999) conducted 8-week open and double-blind
trials administering olanzapine to 44 treatmentresistant patients and treating subsequent
olanzapine-resistant patients with clozapine. Only
5% of patients responded to olanzapine and, of the
remaining patients who were switched to clozapine,
41% responded to clozapine. The authors concluded that non-response to olanzapine does not
predict failure to respond to clozapine. Some open
studies (e.g. Dursun et al, 1999) suggest that
olanzapine might be best used at higher doses in
treatment-resistant schizophrenia.

Quetiapine
There is relatively little published information on
controlled trials of quetiapine v. clozapine in
treatment-resistant patients, but a number of small
trials and case reports suggest its usefulness in
treatment resistance (e.g. Fabre et al, 1995; Brooks,
2001).

Non-clozapine atypicals in combination

At the end of the algorithm shown in Fig. 1, many
clinicians try ad hoc combinations of atypical
antipsychotics for treatment failures with clozapine.
This usually involves a combination of olanzapine
and risperidone. There is a limited published
evidence base on this strategy. Most publications in
this area are case reports and there are likely to be

104

very many unpublished cases where this strategy

has been used in clinical practice. However, Lerner
et al (2004) have attempted to review this scant
literature. They found little evidence other than
anecdotal case reports that augmentation of
clozapine with other atypicals produces any benefit.
Subtracting patients treated with combinations of
clozapine and another atypical leaves a very small
database on which to draw. However, Lerner et al
concluded that there might be some benefit, which
necessitates further controlled studies.

Conclusions
Although olanzapine and risperidone are probably
the most successful antipsychotics for partially
treatment-resistant patients, there is now very
little controversy about the role of clozapine in
more extreme treatment resistance. Indeed, the
NICE schizophrenia guidelines of 2002 strongly
recommend broader and earlier use of clozapine,
suggesting that only one atypical should be tried
before moving onto clozapine.
Most practitioners are now more concerned with
managing clozapine-resistant patients, the focus of
this short review. There is reasonable evidence to
suggest that augmentation strategies with sulpiride,
amisulpride and lamotrigine are useful in treatment
resistance, but no indication as to which patient will
benefit from which strategy. The small proportion
of patients who remain densely resistant to any
pharmacological treatment strategy should probably
be managed by a historical review of their best
treatment regime and the reinstatement of this along
with psychosocial treatments.

References and related articles

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Clozapine pharmacokinetics and pharmacodynamics
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Management of treatment resistant schizophrenia
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Management of clozapine-resistant schizophrenia

Conley, R. R., Tamminga, C. A., Kelly, D. L., et al (1999)

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MCQs
1
a
b
c
d
e

The incidence of treatment-resistant schizophrenia is:

5%
10%
20%
50%
75%.

2 The most commonly used categorical definition of

treatment resistance is :
a prolonged hospitalisation
b less than a 20% improvement on the BPRS
c symptoms enduring for more than 2 years
d persistent negative symptoms
e persistent cognitive symptoms.
3 Definitions of treatment resistance might also
include:
a non-adherence
b failure of maintenance
c comorbidity
d aggression
e negative symptoms.

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105

Kerwin & Bolonna

4 The following drugs show evidence that they are

specific clozapine augmentors:
a aripiprazole
b ziprasidone
c lamotrigne
d zolepine
e amisulpride.

5 The following drugs alone or in combination may

be useful for partial treatment resistance:
a haloperidol at low dose
b risperidone
c olanzapine
d risperidone and olanzapine
e aripiprazole.

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MCQ answers
1
a
b
c
d
e

106

F
F
T
F
F

2
a
b
c
d
e

F
T
F
F
F

3
a
b
c
d
e

T
T
T
F
F

4
a
b
c
d
e

F
F
T
F
T

5
a
b
c
d
e

F
T
T
T
F

Advances in Psychiatric Treatment (2005), vol. 11. http://apt.rcpsych.org/